DMA methylation and associated epigenetic changes lead to functional alterations in pathways that promote neoplastic development. Therapy targeting DMA methylation and histone deacetylation, another epigenetic modification, has shown activity in myeloid leukemias, and is now part of standard of care in patients with myelodysplastic syndrome (MDS). We have identified a DMA hypermethylation signature that characterizes young patients with acute myeloid leukemia (AML) who have a high cure rate following standard cytotoxic chemotherapy. This signature was independent of known prognostic factors and, if validated, would provide an important tool towards personalized therapy in AML. Separately and paradoxically, we have shown that progression in AML (diagnosis to relapse) and in MDS (MDS to AML) is also associated with the progressive acquisition of aberrant DNA methylation that, in this situation, predicts for a poor overall outcome. Finally, in proof-of-concept studies, we have shown that treatment with the DNA methylation inhibitor DAC results in tumor-suppressor gene demethylation and reactivation in AML and MDS, associated with a relatively high response rate that correlates with induction of gene expression of the P15 tumor-suppressor. Based on these observations, we hypothesize that DNA methylation profiling identifies a subset of young patients with AML who are curable with standard chemotherapy. We further hypothesize that DNA methylation, through separate genes, also contributes to clonal evolution in AML, leading to relapses with drug resistant phenotypes, and that DNA methylation inhibition in remission will delay or eliminate clonal evolution and disease relapse in some patients. Finally, we hypothesize that strategies aimed at enhancing pharmacologic epigenetic reactivation will translate into better therapies for myeloid malignancies. To test these hypotheses, we propose the following specific aims: (1) Retrospectively and prospectively validate and extend an epigenetic signature of curability in AML. (2) Conduct a randomized clinical trial of remission maintenance in AML using DAC. (3) Use a methylated and silenced GFP reporter gene selectable system to identify key pathways and pharmacologic combinations that lead to epigenetic reactivation in neoplastic cells. This project will provide new markers of prognosis in AML and new approaches to therapy that are based on incorporating epigenetic modulation into the standard of care of this disease. Lay abstract: DNA methylation is a tag attached to DNA that modifies gene function by preventing RNA formation. Decitabine, a drug that modifies DNA methylation is useful in leukemia. We propose to verify that DNA methylation can identify patients who are curable with chemotherapy. We also propose to use decitabine to prevent relapse in AML, and we will find drugs that boost the activity of decitabine and that can be introduced into clinical trials